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Accepted Manuscript Title: Recent advances in pharmaceutical dosage forms and devices using additive manufacturing technologies Authors: Christos I. Gioumouxouzis, Christina Karavasili, Dimitrios G. Fatouros PII: S1359-6446(18)30216-2 DOI: https://doi.org/10.1016/j.drudis.2018.11.019 Reference: DRUDIS2364 Toappear in: Please cite this article as: Gioumouxouzis, Christos I., Karavasili, Christina, Fatouros, Dimitrios G., Recent advances in pharmaceutical dosage forms and devices using additive manufacturing technologies.Drug Discovery Today https://doi.org/10.1016/j.drudis.2018.11.019 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. Themanuscriptwillundergocopyediting,typesetting,andreviewoftheresultingproof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Recent advances in pharmaceutical dosage forms and devices using additive manufacturing technologies § § * Christos I. Gioumouxouzis , Christina Karavasili and Dimitrios G. Fatouros Department of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece * Corresponding author: Fatouros, D.G. (dfatouro@pharm.auth.gr). §These authors have contributed equally. Highlights: • 3DP has the potential to revolutionize personalized therapy • Rapid increase in 3PD formulations reported during past 5 years • Potential for cost-effective production of elaborate dosage forms • Investigation of the in vivo behavior and cytocompatibility of 3DP formulations • Regulatory landscape concerning commercialization and patient safety still unclear ACCEPTED MANUSCRIPT 1 The era of ‘one-size-fits-all’ treatment approaches is becoming history for pharmaceutical manufacturing with the future encountering a revolution in drug development through the introduction of additive manufacturing technologies. The innovative elements of this disruptive technology will affect all shareholders of the pharmaceutical chain from the industrial sector to the dispensing facilities and, ultimately, the patient end-user. In this review, we provide an overview of the most recent advances in dosage forms and devices using additive manufacturing technologies, along with the regulatory landscape framing the development and safety requirements for 3D-printed drug products before entering the pharmaceutical market. Keywords: 3D printing; dosage forms; routes of administration. Teaser: An outline of the latest advances in additive manufacturing of pharmaceutical dosage forms and the existing regulatory framework. ACCEPTED MANUSCRIPT 2 Introduction 3D printing (3DP) or additive manufacturing (AM) can be any manufacturing process used to transform a 3D digital model into a 3D physical subject by successive material deposition in a layer-by-layer mode. Some of these techniques [e.g., fused deposition modeling (FDM), stereolithography (SLA), binder jetting (BJ), powder bed printing (PBP), semi-solid extrusion (SSE) and inkjet printing (IP)] have been used during the past few years for the creation of pharmaceutical formulations, with the number of published papers increasing at an exponential rate since 2014 [1] (Figure 1). Although drug 3DP technology is still in its infancy, many steps toward the enrollment and optimization of different AM technologies in drug formulation and dosage forms have been taken. For instance, new pharmaceutical-grade polymers were found to be suitable for FDM 3DP operating at much lower temperatures (90°C) than conventional FDM printing, enabling printing of thermolabile active pharmaceutical ingredients (APIs) [2], and a variety of biocompatible bioinks utilized in inkjet 3DP have been developed [3]. The main reason for this burst in AM is the fact that prices of 3D printers are declining steadily and rapidly. The low cost of FDM 3D printers renders them the most suitable candidate for equipping the community pharmacies and other small-scale healthcare provision facilities. Moreover, good manufacturing practices (GMP)-complying FDM printers and hot-melt extruders, for continuous and large-scale drug-loaded filament production, have recently been manufactured [4], highlighting the impending transition from proof-of-concept demonstrations toward real- life applications. ACCEPTED MANUSCRIPT Oral delivery Per os administration, although generally preferred for medication intake, is not ideal for the administration of APIs with a narrow therapeutic window or APIs that exhibit dose-dependent 3
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